US5633360A
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US
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Oligonucleotide analogs capable of passive cell membrane permeation
Assignee: Ionis Pharmaceuticals Inc
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Filing: 1992-04-14
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Granted: 1997-05-27
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Expires: 2012-04-14
Abstract
Abstract Oligonucleotides that are capable of passive diffusion across cell membranes are disclosed. These oligonucleotides contain at least two nucleotide residues and show a log distribution coefficient in octanol:water of about 0.0-2.5 and a solubility in water of at least 0.001 μg/mL. In preferred embodiments, either at least 80% of the internucleotide linkages are non-ionic, or at least 80% of the bases contain lipophilic hydrocarbyl substitutions, or a combination of these sums to 80%. These oligonucleotides may be conjugated to label and used to visualize cells.
Inventors
- 👤 Norbert Bischofberger
- 👤 Ken Kent
- 👤 Rick Wagner
- 👤 Chris Buhr
- 👤 Kuei-Ying Lin
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-09 22:37
CPC Classifications
C; C07; C07H; C07H19/00; C07H19/02; C07H19/04; C07H19/06; C07H21/00
Claims Analysis
Total Claims: 13
Claim 1
Independent Claim
175 words
An oligonucleotide capable of passive diffusion into a cell or a salt thereof wherein said oligonucleotide contains at least two nucleoside residues and wherein said oligonucleotide contains internucleotide linkages selected from the group consisting of phosphodiester, phosphorothioate, phosphorodithioate, formacetal, 3'-thioformacetal, riboacetal, a phosphotriester having a pseudohydrocarbyl substituent (3-20C) and a phosphothiotriester having a pseudohydrocarbyl substituent (3-20C), and further wherein said oligonucleotide is modified such that: at least 60% of the internucleotide linkages are non-ionic internucleotide linkages selected from the group consisting of formacetal, 3'-thioformacetal, riboacetal, a phosphotriester having a pseudohydrocarbyl substituent (3-20C) and a phosphothiotriester having a pseudohydrocarbyl substituent (3-20C); at least 60% of the bases included in said oligonucleotide contain a lipophilic substitution, wherein the lipophilic substitution is at the C5 position of a pyrimidine base or the O4 position of thymine; or the percent non-ionic nucleotide linkage and the percent bases containing lipophilic substitutions sum to at least 60%; said oligonucleotide being characterized by having an log P oct value of about 0.0-2.5 and a solubility in water of at least 0.001 μg/mL.
Claim 2
Dependent Claim
175 words
An oligonucleotide capable of passive diffusion into a cell or a salt thereof wherein said oligonucleotide contains at least two nucleoside residues and wherein said oligonucleotide contains internucleotide linkages selected from the group consisting of phosphodiester, phosphorothioate, phosphorodithioate, formacetal, 3'-thioformacetal, riboacetal, a phosphotriester having a pseudohydrocarbyl substituent (3-20C) and a phosphothiotriester having a pseudohydrocarbyl substituent (3-20C), and further wherein said oligonucleotide is modified such that: at least 60% of the internucleotide linkages are non-ionic internucleotide linkages selected from the group consisting of formacetal, 3'-thioformacetal, riboacetal, a phosphotriester having a pseudohydrocarbyl substituent (3-20C) and a phosphothiotriester having a pseudohydrocarbyl substituent (3-20C); at least 60% of the bases included in said oligonucleotide contain a lipophilic substitution, wherein the lipophilic substitution is at the C5 position of a pyrimidine base or the O4 position of thymine; or the percent non-ionic nucleotide linkage and the percent bases containing lipophilic substitutions sum to at least 60%; said oligonucleotide being characterized by having an log P oct value of about 0.0-2.5 and a solubility in water of at least 0.001 μg/mL.
Claim 3
Dependent Claim
50 words
The oligonucleotide of claim 1 wherein either at least 80% of the internucleotide linkages are non-ionic or at least 80% of the bases included in said nucleosides contain a lipophilic substitution; or wherein the percent non-ionic nucleotide linkage and the percent bases containing lipophilic substitutions sum to at least 80%.
Claim 4
Dependent Claim
36 words
The oligonucleotide of claim 1 wherein said internucleotide linkages are selected from the group consisting of formacetal, 3'-thioformacetal, riboacetal, a phosphotriester containing a pseudohydrocarbyl substituent of 3-20C and a thiophosphotriester containing a pseudohydrocarbyl substituent of 3-20C.
Claim 5
Dependent Claim
33 words
The oligonucleotide of claim 1 wherein at least one nucleoside is selected from the group consisting of thymidine, 2'-deoxycytidine, 2'-deoxy-5-methylcytidine, N 6- methyl-8-oxo-2'-deoxyadenosine, 2'-deoxy-5-vinylcytidine, 2'-deoxy-5-ethynylcytidine, 2'-deoxy-5-vinyluridine, 2'-deoxy-5-propynylcytosine, 2'-deoxy-5-propynyluridine, 2'-deoxy-5'-ethynyluridine, 2'-deoxyadenosine, 2'-deoxyguanosine, and 2'-deoxy-N7-deazaxanthosine.
Claim 6
Dependent Claim
16 words
The oligonucleotide of claim 1 wherein at least one nucleotide is substituted at the 2' position.
Claim 7
Dependent Claim
28 words
The oligonucleotide of claim 5 wherein said 2' substitution is selected from the group consisting of fluoro, O-methyl, O-propyl, O-butyl, S-propyl, S-butyl, S-methyl, O-ethyl, S-ethyl, O-allyl, and S-allyl.
Claim 8
Dependent Claim
12 words
The oligonucleotide of claim 1 which is a dimer, trimer or tetramer.
Claim 9
Dependent Claim
13 words
The oligonucleotide of claim 1 wherein the log Poct value is about 1.0-2.2.
Claim 10
Dependent Claim
50 words
The oligonucleotide of claim 8 wherein either at least 80% of the internucleotide linkages are non-ionic or at least 80% of the bases included in said nucleosides contain the lipophilic substitution, or wherein the percent non-ionic nucleotide linkage and the percent bases containing lipophilic substitutions sum to at least 80%.
Claim 11
Dependent Claim
20 words
The oligonucleotide of claim 9 wherein said internucleotide linkages are selected from the group consisting of phosphodiester, phosphorothioate, and formacetal.
Claim 12
Dependent Claim
36 words
The oligonucleotide of claim 8 wherein at least one nucleoside is selected from the group consisting of thymidine, 2'-deoxycytidine, 2'-deoxy-5-methylcytidine, N 6 -methyl-8-oxo-2'-deoxyadenosine, 2'-deoxy-5-vinylcytidine, 2'-deoxy-5-ethynylcytidine, 2'-deoxy-5-vinyluridine, 2'-deoxy-5-vinyluridine, 2'-deoxy-5-propynylcytidine, 2'-deoxy-5-propynyluridine, 2'-deoxy-5-ethynyluridine, 2'-deoxyadenosine, 2'-deoxyguanosine, and 2'-deoxy-N 7 -deazaxanthosine.
Claim 13
Dependent Claim
16 words
The oligonucleotide of claim 8 wherein at least one nucleoside is substituted at the 2' position.
References Cited (Backward Citations)
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WO1989012060A1
Cited
WO1990010448A2
Cited
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Cited
US5420330A
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 2000-05-26 | 2000-11-25 | 2001-05-27 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2004-05-26 | 2004-11-25 | 2005-05-27 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2008-05-26 | 2008-11-25 | 2009-05-27 | $7700.00 | Window Closed / Lapsed |